Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity

Abstract

Vascular integrity helps maintain brain microenvironment homeostasis, which is critical for the normal development and function of the central nervous system. It is known that neural cells can regulate brain vascular integrity. However, due to the high complexity of neurovascular interactions involved, understanding of the neural regulation of brain vascular integrity is still rudimentary. Using intact zebrafish larvae and cultured rodent brain cells, we find that neurons transfer miR-132, a highly conserved and neuron-enriched microRNA, via secreting exosomes to endothelial cells (ECs) to maintain brain vascular integrity. Following translocation to ECs through exosome internalization, miR-132 regulates the expression of vascular endothelial cadherin (VE-cadherin), an important adherens junction protein, by directly targeting eukaryotic elongation factor 2 kinase (eef2k). Disruption of neuronal miR-132 expression or exosome secretion, or overexpression of vascular eef2k impairs VE-cadherin expression and brain vascular integrity. Our study indicates that miR-132 acts as an intercellular signal mediating neural regulation of the brain vascular integrity and suggests that the neuronal exosome is a novel avenue for neurovascular communication.

Combining feature selection and shape analysis uncovers precise rules for miRNA regulation in Huntington’s disease mice

“…strong and linear effects) of expression in the surface defined by CAG-repeat lengths and age points in the striatum of these mice. This conclusion is reminiscent of a similar trend detected in the brain of wild-type mice, where miRNA regulation may be poorly correlated to gene expression signatures across cell types [38]. This conclusion is even more stringent for the cortex of Hdh mice, suggesting that miRNA regulation do not play a critical role in truly responding to HD in this brain area.…”

“…Although we cannot exclude the possibility that the conclusion about a limited global role of miRNA regulation in the brain of Hdh mice might be biased by the current lack of cell-type specific RNA-seq data in HD mice, our data highlight a new set of precisely matched and highly prioritized miRNA-target relationships (see Figure 2, Table S3) that are known to play a role in neuronal activity and homeostasis. This feature applies to miRNAs that are upregulated in the striatum of Motif-Containing ProteinTrim26) is associated to brain vascular integrity in zebrafish [38], spine density [39] and synaptogenesis [40]. Knocking down Mir1b (upregulated and paired with Ventral Anterior Homeobox 2, Vax2) significantly alleviated neuronal death induced by hypoxia [41].…”

Extracellular microRNAs as messengers in the central and peripheral nervous system

“…Neuronal exosomes produced following neuronal activity were also taken up by astrocytes where GLT1 was up-regulated as a result, potentially via the indirect action of exosomal miR-124a [31]. Furthermore, neuronal miR-132 packaged into exosomes was found to be internalized by endothelial cells where it altered gene expression and regulated brain vascular integrity [35]. Taken together, these studies point towards a role of extracellular microRNAs in neuronal activity as well as brain development and maintenance.…”

“…They are actively secreted by healthy cells, including cells of the nervous system [31][32][33][34][35], and can be taken up by neighbouring cells or even other tissues, where they are functionally active [31,[36][37][38][39][40][41]. Hence, extracellular microRNAs have the potential to act as messengers over both short and long distances [9][10][11].…”

Remote control of BBB: A tale of exosomes and microRNA

“…In a recent paper in Cell Research, Xu and colleagues [11] used zebrafish as a model system to examine the function of miR-132, a microRNA predominantly expressed in neurons. By antagonizing miR-132 with morpholino antisense oligonucleotides, they surprisingly found that zebrafish larvae with inactivated miR-132 (miR-132 morphants) exhibited severe intracranial hemorrhage and impaired BBB integrity, as shown by extravasation of red blood cells and brain accumulation of exogenous circulating tracers.…”